Identification

Name
Indomethacin
Accession Number
DB00328  (APRD00109)
Type
Small Molecule
Groups
Approved, Investigational
Description

Indomethacin is a non-steroidal antiinflammatory agent (NSAIA) with antiinflammatory, analgesic and antipyretic activity. Its pharmacological effect is thought to be mediated through inhibition of the enzyme cyclooxygenase (COX), the enzyme responsible for catalyzes the rate-limiting step in prostaglandin synthesis via the arachidonic acid pathway.

Structure
Thumb
Synonyms
  • {1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl}acetic acid
  • 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid
  • Aconip
  • Indometacin
  • Indometacina
  • Indometacine
  • Indometacinum
  • Indomethacin
External IDs
NSC-77541
Product Ingredients
IngredientUNIICASInChI Key
Indomethacin sodium0IMX38M2GG74252-25-8UHYAQBLOGVNWNT-UHFFFAOYSA-M
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo Indomethacin Cap 25mgCapsule25 mgOralApotex Corporation1984-12-31Not applicableCanada
Apo Indomethacin Cap 50mgCapsule50 mgOralApotex Corporation1984-12-31Not applicableCanada
Indocid Cap 25mgCapsule25 mgOralMerck Frosst Canada & Cie, Merck Frosst Canada & Co.1965-12-311998-08-14Canada
Indocid Cap 50mgCapsule50 mgOralMerck Frosst Canada & Cie, Merck Frosst Canada & Co.1970-12-311998-08-14Canada
Indocid SR 75mgCapsule, extended release75 mgOralMerck Frosst Canada & Cie, Merck Frosst Canada & Co.1980-12-311999-08-06Canada
Indocid Sterile Oph Susp 1%Solution / drops10 mgOphthalmicMerck Frosst Canada & Cie, Merck Frosst Canada & Co.1983-12-311999-08-06Canada
Indocid Sup 100mgSuppository100 mgRectalMerck Frosst Canada & Cie, Merck Frosst Canada & Co.1971-12-312003-08-08Canada
Indocid Sup 50mgSuppository50 mgRectalMerck Frosst Canada & Cie, Merck Frosst Canada & Co.1983-12-312003-08-08Canada
IndocinCapsule50 mg/1OralMerck & Co., Inc.2006-09-192006-09-19Us
IndocinSuppository50 mg/1RectalMerck & Co., Inc.2006-09-192006-09-19Us
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Ftp-indomethacinCapsule25 mgOralFtp Pharmacal Inc.1998-10-092004-08-03Canada
Ftp-indomethacinCapsule50 mgOralFtp Pharmacal Inc.1998-10-092004-08-03Canada
IndocinSuppository50 mg/1RectalIroko Pharmaceuticals, LLC1992-08-31Not applicableUs
IndomethacinCapsule25 mg/1OralNucare Pharmaceuticals, Inc.2011-11-01Not applicableUs
IndomethacinCapsule50 mg/1OralPreferreed Pharmaceuticals Inc.2016-08-05Not applicableUs
IndomethacinCapsule25 mg/1OralREMEDYREPACK INC.2018-10-03Not applicableUs
IndomethacinCapsule50 mg/1OralDenton Pharma, Inc. Dba Northwind Pharmaceuticals2018-10-26Not applicableUs
IndomethacinCapsule50 mg/1OralRemedy Repack2013-03-182014-03-18Us
IndomethacinCapsule, extended release75 mg/1OralActavis Pharma Company2014-01-012015-11-30Us
IndomethacinCapsule50 mg/1OralZydus Pharmaceuticals Usa, Inc.2016-07-21Not applicableUs
International/Other Brands
Arthrexin (Alphapharm) / Elmetacin (Sankyo) / Indaflex (Andromaco) / Indocid (Lundbeck) / Indocin / Indolar SR (Sandoz) / Indomed (Greater Pharma) / Indoxen (Quality Pharmaceutical) / Metindol (GlaxoSmithKline) / Mikametan (Mikasa Seiyaku) / Nu-Indo (Nu-Pharm) / Reumacide (Vitória)
Categories
UNII
XXE1CET956
CAS number
53-86-1
Weight
Average: 357.788
Monoisotopic: 357.076785712
Chemical Formula
C19H16ClNO4
InChI Key
CGIGDMFJXJATDK-UHFFFAOYSA-N
InChI
InChI=1S/C19H16ClNO4/c1-11-15(10-18(22)23)16-9-14(25-2)7-8-17(16)21(11)19(24)12-3-5-13(20)6-4-12/h3-9H,10H2,1-2H3,(H,22,23)
IUPAC Name
2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid
SMILES
COC1=CC2=C(C=C1)N(C(=O)C1=CC=C(Cl)C=C1)C(C)=C2CC(O)=O

Pharmacology

Indication

For moderate to severe rheumatoid arthritis including acute flares of chronic disease, ankylosing spondylitis, osteoarthritis, acute painful shoulder (bursitis and/or tendinitis) and acute gouty arthritis.

Associated Conditions
Pharmacodynamics

Indomethacin, a NSAIA, with analgesic and antipyretic properties exerts its pharmacological effects by inhibiting the synthesis of prostaglandins involved in pain, fever, and inflammation. Indomethacin inhibits the catalytic activity of the COX enzymes, the enzymes responsible for catalyzing the rate-limiting step in prostaglandin synthesis via the arachidonic acid pathway. Indomethacin is known to inhibit two well-characterized isoforms of COX, COX-1 and COX-2, with greater selectivity for COX-1. COX-1 is a constitutively expressed enzyme that is involved in gastric mucosal protection, platelet and kidney function. It catalyzes the conversion of arachidonic acid to prostaglandin (PG) G2 and PGG2 to PGH2. COX-1 is involved in the synthesis pathways of PGE2, PGD2, PDF2a, PGI2 (also known as prostacyclin) and thromboxane A2 (TXA2). COX-2 is constitutively expressed and highly inducible by inflammatory stimuli. It is found in the central nervous system, kidneys, uterus and other organs. It also catalyzes the conversion of arachidonic acid to PGG2 and PGG2 to PGH2. In the COX-2-mediated pathway, PGH2 is subsequently converted to PGE2 and PGI2 (also known as prostacyclin). PGE2 is involved in mediating inflammation, pain and fever. Decreasing levels of PGE2 leads to decreased inflammation.

Mechanism of action

Indomethacin is a prostaglandin G/H synthase (also known as cyclooxygenase or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). Prostaglandin G/H synthase catalyzes the conversion of arachidonic acid to a number of prostaglandins involved in fever, pain, swelling, inflammation, and platelet aggregation. Indomethacin antagonizes COX by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Indomethacin, unlike other NSAIDs, also inhibits phospholipase A2, the enzyme responsible for releasing arachidonic acid from phospholipids. Indomethacin is more selective for COX-1 than COX-2, which accounts for its increased adverse gastric effects relative to other NSAIDs. COX-1 is required for maintaining the protective gastric mucosal layer. The analgesic, antipyretic and anti-inflammatory effects of indomethacin occur as a result of decreased prostaglandin synthesis. Its antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation.

TargetActionsOrganism
UProstaglandin G/H synthase 1
inhibitor
Human
AProstaglandin G/H synthase 2
inhibitor
Human
APhospholipase A2, membrane associated
inhibitor
Human
UProstaglandin reductase 2
inhibitor
Human
UPeroxisome proliferator-activated receptor gamma
activator
Human
ULactoylglutathione lyase
inhibitor
Human
UProstaglandin D2 receptor 2
other/unknown
Human
UPeroxisome proliferator-activated receptor alpha
agonist
Human
UAldo-keto reductase family 1 member C3
inhibitor
Human
Absorption

Bioavailability is approximately 100% following oral administration and 80–90% following rectal administration.

Volume of distribution
Not Available
Protein binding

97%

Metabolism

Hepatic.

Route of elimination

Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion.

Half life

4.5 hours

Clearance
Not Available
Toxicity

The following symptoms may be observed following overdosage: nausea, vomiting, intense headache, dizziness, mental confusion, disorientation, or lethargy. There have been reports of paresthesias, numbness, and convulsions. The oral LD50 of indomethacin in mice and rats (based on 14 day mortality response) was 50 and 12 mg/kg, respectively.

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Indomethacin Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of gastrointestinal bleeding can be increased when Indomethacin is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of gastrointestinal bleeding can be increased when Indomethacin is combined with (S)-Warfarin.
2,4-thiazolidinedioneThe risk or severity of hypoglycemia can be increased when Indomethacin is combined with 2,4-thiazolidinedione.
4-hydroxycoumarinThe risk or severity of gastrointestinal bleeding can be increased when Indomethacin is combined with 4-hydroxycoumarin.
AbacavirIndomethacin may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbciximabThe risk or severity of bleeding and hemorrhage can be increased when Indomethacin is combined with Abciximab.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Indomethacin.
AbirateroneThe metabolism of Indomethacin can be decreased when combined with Abiraterone.
AcarboseIndomethacin may decrease the excretion rate of Acarbose which could result in a higher serum level.
AcebutololIndomethacin may decrease the antihypertensive activities of Acebutolol.
Food Interactions
  • Avoid alcohol.
  • Take with food or antacids to reduce irritation.

References

Synthesis Reference

Hubertus L. Regtop, John R. Biffin, "Preparation of divalent metal salts of indomethacin." U.S. Patent US5310936, issued November, 1917.

US5310936
General References
  1. Akbarpour F, Afrasiabi A, Vaziri ND: Severe hyperkalemia caused by indomethacin and potassium supplementation. South Med J. 1985 Jun;78(6):756-7. [PubMed:4002013]
  2. HART FD, BOARDMAN PL: INDOMETHACIN: A NEW NON-STEROID ANTI-INFLAMMATORY AGENT. Br Med J. 1963 Oct 19;2(5363):965-70. [PubMed:14056924]
  3. Lum GM, Aisenbrey GA, Dunn MJ, Berl T, Schrier RW, McDonald KM: In vivo effect of indomethacin to potentiate the renal medullary cyclic AMP response to vasopressin. J Clin Invest. 1977 Jan;59(1):8-13. [PubMed:187624]
  4. Phelan KM, Mosholder AD, Lu S: Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs. J Clin Psychiatry. 2003 Nov;64(11):1328-34. [PubMed:14658947]
  5. Ragheb M: The clinical significance of lithium-nonsteroidal anti-inflammatory drug interactions. J Clin Psychopharmacol. 1990 Oct;10(5):350-4. [PubMed:2258452]
External Links
Human Metabolome Database
HMDB0014473
KEGG Drug
D00141
KEGG Compound
C01926
PubChem Compound
3715
PubChem Substance
46508291
ChemSpider
3584
BindingDB
17638
ChEBI
49662
ChEMBL
CHEMBL6
Therapeutic Targets Database
DAP000617
PharmGKB
PA449982
IUPHAR
1909
Guide to Pharmacology
GtP Drug Page
HET
IMN
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Indomethacin
ATC Codes
S01CC02 — Indometacin and antiinfectivesM02AA23 — IndometacinM01AB01 — IndometacinM01AB51 — Indometacin, combinationsS01BC01 — IndometacinC01EB03 — Indometacin
AHFS Codes
  • 28:08.04.92 — Other Nonsteroidal Antiimflammatory Agents
PDB Entries
1s2a / 1z9h / 2bxk / 2bxm / 2bxq / 2dm6 / 2oth / 2zb8 / 3ads / 3adx
show 14 more
FDA label
Download (56.2 KB)
MSDS
Download (73.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0Not Yet RecruitingTreatmentPremature Labour1
0RecruitingOtherCerebrovascular Circulation1
0Unknown StatusDiagnosticGastrointestinal Diseases1
1Active Not RecruitingTreatmentBreast Neoplasm, Male / Neoplasms, Breast / Triple Negative Breast Cancer (TNBC)1
1CompletedNot AvailableAutonomic Failure / Idiopathic orthostatic hypotension1
1CompletedBasic ScienceAcute Gouty Arthritis1
1CompletedOtherNeoplasms, Colorectal / Neoplasms, Esophageal / Neoplasms, Ovarian1
1Not Yet RecruitingBasic ScienceHealthy Volunteers1
1RecruitingBasic ScienceImpaired Small Intestinal Permeability1
1, 2Active Not RecruitingTreatmentChronic Orthostatic Intolerance / Tachycardia1
1, 2CompletedBasic ScienceCardiovascular Disease (CVD) / High Blood Pressure (Hypertension) / Obstructive Sleep Apnea (OSA) / Strokes1
1, 2CompletedTreatmentObstetric Labour, Premature1
1, 2RecruitingPreventionBrain Injury / Intraventricular Hemorrhage / Periventricular Leukomalacia / Renal Injury1
1, 2RecruitingTreatmentMetastatic Hormone Refractory Prostate Cancer / Recurrent Prostate Carcinoma / Stage IV Prostate Cancer1
1, 2TerminatedTreatmentMucinous Adenocarcinoma of the Colon / Mucinous Adenocarcinoma of the Rectum / Recurrent Colon Cancer / Recurrent Rectal Cancer / Signet Ring Adenocarcinoma of the Colon / Signet Ring Adenocarcinoma of the Rectum / Stage IVA Colon Cancer / Stage IVA Rectal Cancer / Stage IVB Colon Cancer / Stage IVB Rectal Cancer1
2Active Not RecruitingTreatmentSquamous Cell Carcinoma of the Oral Cavity1
2CompletedPreventionPatent Ductus Arteriosus (PDA)1
2CompletedTreatmentMelanoma (Skin)1
2CompletedTreatmentPostoperative pain1
2CompletedTreatmentPreterm Labor With Intact Membranes1
2CompletedTreatmentSquamous Cell Carcinoma of the Head and Neck (SCCHN)1
2RecruitingBasic ScienceAsthma Bronchial / Electrophilic Fatty Acids1
2RecruitingTreatmentCervical Squamous Cell Carcinoma In Situ / Vulvar High Grade Squamous Intraepithelial Lesion1
2RecruitingTreatmentPreterm Premature Rupture of Membranes1
2RecruitingTreatmentStage III Prostate Adenocarcinoma / Stage III Prostate Adenocarcinoma AJCC v7 / Stage III Prostate Cancer / Stage III Prostate Cancer AJCC v7 / Stage IV Prostate Adenocarcinoma / Stage IV Prostate Adenocarcinoma AJCC v7 / Stage IV Prostate Cancer / Stage IV Prostate Cancer AJCC v71
2Unknown StatusDiagnosticElectroencephalography / Premature Births / Regional Blood Flow1
2Unknown StatusTreatmentPatent Ductus Arteriosus (PDA)1
2WithdrawnTreatmentAcute Gouty Arthritis1
2WithdrawnTreatmentPatent Ductus Arteriosus (PDA)1
2, 3CompletedPreventionPost-ERCP Pancreatitis1
2, 3RecruitingPreventionDifficult Embryo Transfer1
2, 3RecruitingTreatmentLangerhans Cell Histiocytosis (LCH)1
2, 3TerminatedTreatmentPatent Ductus Arteriosus (PDA)1
3CompletedPreventionBleeding in the Brain / Infants, Premature / Intraventricular Hemorrhage (IVH) / Very Low Birth Weight Infants1
3CompletedPreventionInfants, Premature / Patent Ductus Arteriosus (PDA) / Very Low Birth Weight Infant1
3CompletedPreventionPost-ERCP Acute Pancreatitis1
3CompletedTreatmentAcute Gout Flare1
3CompletedTreatmentAcute Gouty Arthritis1
3CompletedTreatmentAlzheimer's Disease (AD)1
3CompletedTreatmentAnkylosing Spondylitis (AS)1
3CompletedTreatmentCardiovascular Disease (CVD) / Defect, Congenital Heart / Heart Diseases / Patent Ductus Arteriosus (PDA)1
3CompletedTreatmentOther Acute Postoperative Pain2
3CompletedTreatmentPost ERCP Acute Pancreatitis1
3CompletedTreatmentOcular inflammatory conditions1
3Not Yet RecruitingPreventionPost ERCP Pancreatitis1
3RecruitingPreventionDifficult Embryo Transfer1
3RecruitingTreatmentAcute Pancreatitis (AP)1
3RecruitingTreatmentPatent Ductus Arteriosus (PDA)1
3RecruitingTreatmentRefractory Chronic Cough1
3TerminatedPreventionPost-ERCP Acute Pancreatitis1
3Unknown StatusTreatmentObstetric Labour, Premature1
3Unknown StatusTreatmentPain NOS / Renal Colic1
4CompletedNot AvailablePatent Ductus Arteriosus (PDA) / Prematurity of Fetus1
4CompletedBasic ScienceHealthy Males / Neuromuscular Function2
4CompletedPreventionAcute Pancreatitis (AP)1
4CompletedPreventionCataracts / Inflammatory Reaction1
4CompletedPreventionFamily Planning1
4CompletedPreventionHealthy Volunteers1
4CompletedSupportive CareHemorrhage1
4CompletedTreatmentAnkle Sprains1
4CompletedTreatmentColorectal Cancers1
4CompletedTreatmentEnuresis1
4CompletedTreatmentMacular Edema (ME)1
4CompletedTreatmentPost-Operative Pain1
4Not Yet RecruitingTreatmentAcute Pancreatitis (AP)1
4Not Yet RecruitingTreatmentAcute Pancreatitis (AP) / Gastrointestinal Diseases1
4RecruitingPreventionPancreatitis1
4RecruitingTreatmentAnkylosing Spondylitis (AS) / Spondyloarthritis, Axial1
4RecruitingTreatmentPremature Labour1
4TerminatedPreventionPost-ERCP Pancreatitis1
4TerminatedPreventionPremature Labour1
4WithdrawnTreatmentPatent Ductus Arteriosus (PDA) / Very Low Birth Weight Infants1
Not AvailableActive Not RecruitingTreatmentObstetric Labour, Premature1
Not AvailableCompletedNot AvailableHealthy Volunteers1
Not AvailableCompletedOtherDehydration / Indomethacin1
Not AvailableCompletedPreventionPost-ERCP Acute Pancreatitis1
Not AvailableCompletedTreatmentCervical Insufficiency1
Not AvailableCompletedTreatmentKnee Osteoarthritis (Knee OA)1
Not AvailableCompletedTreatmentNephrogenic Diabetes Insipidus1
Not AvailableCompletedTreatmentPancreatitis1
Not AvailableCompletedTreatmentPremature Labour1
Not AvailableRecruitingPreventionPancreatitis1
Not AvailableRecruitingTreatmentElbow Trauma Requiring Operative Management1
Not AvailableRecruitingTreatmentPatent Ductus Arteriosus (PDA)1
Not AvailableTerminatedPreventionEndoscopic Retrograde Cholangiopancreatography / Pancreatitis1
Not AvailableTerminatedTreatmentPatent Ductus Arteriosus (PDA) / Preterm, Infant1
Not AvailableUnknown StatusNot AvailableLow Responders / Mild to Moderate Male Factor Infertility / Primary Infertility / Secondary Infertility1

Pharmacoeconomics

Manufacturers
  • Iroko pharmaceuticals llc
  • Sandoz inc
  • Able laboratories inc
  • Avanthi inc
  • Inwood laboratories inc sub forest laboratories inc
  • Teva pharmaceuticals usa inc
  • Duramed pharmaceuticals inc sub barr laboratories inc
  • Halsey drug co inc
  • Heritage pharmaceuticals inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mutual pharmaceutical co inc
  • Mylan pharmaceuticals inc
  • Parke davis div warner lambert co
  • Pioneer pharmaceuticals inc
  • Pliva inc
  • Roxane laboratories inc
  • Superpharm corp
  • Vintage pharmaceuticals llc
  • Watson laboratories inc
  • App pharmaceuticals llc
  • G and w laboratories inc
  • Lundbeck inc
  • Bedford laboratories div ben venue laboratories inc
Packagers
  • Advanced Pharmaceutical Services Inc.
  • Amerisource Health Services Corp.
  • Apotheca Inc.
  • Apothecary Shop Wholesale
  • A-S Medication Solutions LLC
  • Bedford Labs
  • Bryant Ranch Prepack
  • Cardinal Health
  • Caremark LLC
  • Central Texas Community Health Centers
  • Comprehensive Consultant Services Inc.
  • DHHS Program Support Center Supply Service Center
  • Direct Dispensing Inc.
  • Dispensing Solutions
  • Emcure Pharmaceuticals Ltd.
  • Endo Pharmaceuticals Inc.
  • Eon Labs
  • G & W Labs
  • Group Health Cooperative
  • H.J. Harkins Co. Inc.
  • Heartland Repack Services LLC
  • Inwood Labs
  • Iroko Pharmaceuticals
  • Kaiser Foundation Hospital
  • KVK-Tech Inc.
  • Lake Erie Medical and Surgical Supply
  • Liberty Pharmaceuticals
  • Lundbeck Inc.
  • Major Pharmaceuticals
  • Medisca Inc.
  • Medvantx Inc.
  • Merck & Co.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Novopharm Ltd.
  • Nucare Pharmaceuticals Inc.
  • Palmetto Pharmaceuticals Inc.
  • Patient First Corp.
  • PCA LLC
  • PD-Rx Pharmaceuticals Inc.
  • Pharmedix
  • Physicians Total Care Inc.
  • Pliva Inc.
  • Preferred Pharmaceuticals Inc.
  • Prepackage Specialists
  • Prescription Dispensing Service Inc.
  • Qualitest
  • Rebel Distributors Corp.
  • Redpharm Drug
  • Remedy Repack
  • Sandhills Packaging Inc.
  • Sandoz
  • Southwood Pharmaceuticals
  • St Mary's Medical Park Pharmacy
  • Talbert Medical Management Corp.
  • Teva Pharmaceutical Industries Ltd.
  • Tya Pharmaceuticals
  • UDL Laboratories
  • United Research Laboratories Inc.
  • Veratex Corp.
Dosage forms
FormRouteStrength
Capsule, extended releaseOral75 mg
Solution / dropsOphthalmic10 mg
Injection, powder, lyophilized, for solutionIntravenous1 mg/1
SuspensionOral25 mg/5mL
Liquid; powder, for solutionOphthalmic1 mg
CapsuleOral25 mg/1
CapsuleOral50 mg/1
Capsule, extended releaseOral75 mg/1
Injection, powder, for solutionIntravenous0.1 mg/0.1mL
Injection, powder, lyophilized, for solutionIntravenous1 mg/1mL
SuppositoryRectal50 mg/1
CapsuleOral75 mg/1
CapsuleOral25 mg
CapsuleOral50 mg
SuppositoryRectal100 mg
SuppositoryRectal50 mg
CapsuleOral20 mg/1
CapsuleOral40 mg/1
Prices
Unit descriptionCostUnit
Indocin i.v. 1 mg vial642.6USD vial
Indomethacin 1 mg vial600.0USD vial
Indocin 50 mg suppository9.56USD suppository
Indomethacin CR 75 mg capsule3.12USD capsule
Indocin sr 75 mg capsule2.92USD capsule
Indomethacin powder2.57USD g
Ratio-Indomethacin 100 mg Suppository0.93USD suppository
Sandoz Indomethacin 100 mg Suppository0.93USD suppository
Sandoz Indomethacin 50 mg Suppository0.93USD suppository
Indomethacin 50 mg capsule0.65USD capsule
Indomethacin 25 mg capsule0.44USD capsule
Apo-Indomethacin 50 mg Capsule0.16USD capsule
Novo-Methacin 50 mg Capsule0.16USD capsule
Nu-Indo 50 mg Capsule0.16USD capsule
Apo-Indomethacin 25 mg Capsule0.09USD capsule
Novo-Methacin 25 mg Capsule0.09USD capsule
Nu-Indo 25 mg Capsule0.09USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9089471No2015-07-282030-04-23Us
US8992982No2015-03-312030-04-23Us
US8734847No2014-05-272030-04-23Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)151U.S. Patent 3,161,654.
water solubility0.937 mg/L (at 25 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP4.27HANSCH,C ET AL. (1995)
logS-4.62ADME Research, USCD
Caco2 permeability-4.69ADME Research, USCD
pKa4.5BUDAVARI,S ET AL. (1989)
Predicted Properties
PropertyValueSource
Water Solubility0.0024 mg/mLALOGPS
logP4.25ALOGPS
logP3.53ChemAxon
logS-5.2ALOGPS
pKa (Strongest Acidic)3.8ChemAxon
pKa (Strongest Basic)-2.3ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area68.53 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity94.81 m3·mol-1ChemAxon
Polarizability36.64 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9509
Blood Brain Barrier+0.9381
Caco-2 permeable+0.5857
P-glycoprotein substrateNon-substrate0.636
P-glycoprotein inhibitor INon-inhibitor0.9313
P-glycoprotein inhibitor IINon-inhibitor0.834
Renal organic cation transporterNon-inhibitor0.8334
CYP450 2C9 substrateNon-substrate0.712
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.6436
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9302
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6978
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.8728
BiodegradationNot ready biodegradable0.9743
Rat acute toxicity4.0722 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9818
hERG inhibition (predictor II)Non-inhibitor0.8306
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (7.7 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-002f-9100000000-2545b33ef519ca9557d7
Mass Spectrum (Electron Ionization)MSsplash10-000i-1901000000-710010c41f0ded9b0f17
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-03di-0009000000-5a4abda1542473813a5d
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-03di-0019000000-b80206e17a22fdf15299
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-0002-0093000000-4e04725a4a7ea8db1880
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-0bt9-0906000000-44825d096b6f8c6091ab
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-053r-0890000000-e9f8e33084842b2a91e0
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-0a4i-0900000000-5aee2869a858e70aa8cb
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-0a4i-0900000000-5aee2869a858e70aa8cb
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-03di-0019000000-b9916635c4db449698ab
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-0002-0092000000-270cd44f32c881ded6aa
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-0a4j-0973000000-6e9ac766080e35c8b297
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-053r-0790000000-b0e6139fc1746c17ddb7
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-0a4i-0900000000-1df95eb7ff5058a870cc
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-03di-0009000000-6a65e96ca253d6a3dda0
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-08gi-0195000000-7ea82149ddaa783e01df
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00di-0900000000-1208c0d5e605b8b69605
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4r-0709000000-1814b324e15b59fa31a5
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0900000000-da84cf2df3db68610ae6
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0900000000-f05d502a85960fefa1b3
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0900000000-ef4bc1155685673e5c96
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-1900000000-f3d47b27b5deef302e24
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-1900000000-529c521348d72ac3ac2c
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4r-0709000000-552147af435f6203b275
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0900000000-3ecb36f2b39a0a31490e
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0900000000-3f989b1435664e5bd1c9
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0900000000-432dc50c7beda844e96f
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0900000000-3a2c27afaa406477bb36
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-1900000000-30707a04c6d14ccc1494
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00di-0900000000-ceb3b04d9de59607c950
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000i-2902000000-8effecdaf737eb86e781
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000i-0901000000-aa0cdbd9e10c432d837c
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000i-3900000000-353e94b605ae82792fae
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-000i-0901000000-5c9675c7c76c033ffc5b
1H NMR Spectrum1D NMRNot Applicable
13C NMR Spectrum1D NMRNot Applicable

Taxonomy

Description
This compound belongs to the class of organic compounds known as benzoylindoles. These are organic compounds containing an indole attached to a benzoyl moiety through the acyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Benzoylindoles
Direct Parent
Benzoylindoles
Alternative Parents
Indole-3-acetic acid derivatives / Indolecarboxylic acids and derivatives / 3-alkylindoles / 4-halobenzoic acids and derivatives / Anisoles / Benzoyl derivatives / Alkyl aryl ethers / Chlorobenzenes / Substituted pyrroles / Aryl chlorides
show 10 more
Substituents
Benzoylindole / Indole-3-acetic acid derivative / Indolecarboxylic acid derivative / Indolyl carboxylic acid derivative / 4-halobenzoic acid or derivatives / Halobenzoic acid or derivatives / 3-alkylindole / Indole / Benzoic acid or derivatives / Anisole
show 27 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
aromatic ether, monochlorobenzenes, N-acylindole, indole-3-acetic acids (CHEBI:49662) / a small molecule (CPD-10545)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gas...
Gene Name
PTGS1
Uniprot ID
P23219
Uniprot Name
Prostaglandin G/H synthase 1
Molecular Weight
68685.82 Da
References
  1. Bobadilla L RA, Perez-Alvarez V, Bracho Valdes I, Lopez-Sanchez P: Effect of pregnancy on the roles of nitric oxide and prostaglandins in 5-hydroxytryptamine-induced contractions in rat isolated thoracic and abdominal aorta. Clin Exp Pharmacol Physiol. 2005 Mar;32(3):202-9. [PubMed:15743404]
  2. Fornai M, Blandizzi C, Colucci R, Antonioli L, Bernardini N, Segnani C, Baragatti B, Barogi S, Berti P, Spisni R, Del Tacca M: Role of cyclooxygenases 1 and 2 in the modulation of neuromuscular functions in the distal colon of humans and mice. Gut. 2005 May;54(5):608-16. [PubMed:15831902]
  3. Higuchi K, Tominaga K, Watanabe T, Uno H, Shiba M, Sasaki E, Tanigawa T, Takashima T, Hamaguchi M, Oshitani N, Matsumoto T, Iwanaga Y, Fukuda T, Fujiwara Y, Arakawa T: Indomethacin, but not Helicobacter pylori, inhibits adaptive relaxation in isolated guinea-pig stomach. Drugs Exp Clin Res. 2004;30(5-6):235-41. [PubMed:15700751]
  4. Kundu N, Walser TC, Ma X, Fulton AM: Cyclooxygenase inhibitors modulate NK activities that control metastatic disease. Cancer Immunol Immunother. 2005 Oct;54(10):981-7. Epub 2005 May 13. [PubMed:15891886]
  5. Moth CW, Prusakiewicz JJ, Marnett LJ, Lybrand TP: Stereoselective binding of indomethacin ethanolamide derivatives to cyclooxygenase-1. J Med Chem. 2005 May 19;48(10):3613-20. [PubMed:15887968]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and...
Gene Name
PTGS2
Uniprot ID
P35354
Uniprot Name
Prostaglandin G/H synthase 2
Molecular Weight
68995.625 Da
References
  1. Armstrong PJ, Franklin DP, Carey DJ, Elmore JR: Suppression of experimental aortic aneurysms: comparison of inducible nitric oxide synthase and cyclooxygenase inhibitors. Ann Vasc Surg. 2005 Mar;19(2):248-57. [PubMed:15770365]
  2. Jerde TJ, Calamon-Dixon JL, Bjorling DE, Nakada SY: Celecoxib inhibits ureteral contractility and prostanoid release. Urology. 2005 Jan;65(1):185-90. [PubMed:15667901]
  3. Pilane CM, Labelle EF: Nitric oxide stimulated vascular smooth muscle cells undergo apoptosis induced in part by arachidonic acid derived eicosanoids. J Cell Physiol. 2005 Aug;204(2):423-7. [PubMed:15668944]
  4. Yokota A, Taniguchi M, Takahira Y, Tanaka A, Takeuchi K: Rofecoxib produces intestinal but not gastric damage in the presence of a low dose of indomethacin in rats. J Pharmacol Exp Ther. 2005 Jul;314(1):302-9. Epub 2005 Apr 14. [PubMed:15831440]
  5. Zhang GS, Fu YB, Xia M: [Proliferation inhibition effect of indomethacin on CML cells associated with down-regulation of phosphorylated STAT1/STAT5 and inhibition of COX-2 expression]. Zhonghua Xue Ye Xue Za Zhi. 2004 Dec;25(12):732-5. [PubMed:15730717]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Phospholipid binding
Specific Function
Thought to participate in the regulation of the phospholipid metabolism in biomembranes including eicosanoid biosynthesis. Catalyzes the calcium-dependent hydrolysis of the 2-acyl groups in 3-sn-ph...
Gene Name
PLA2G2A
Uniprot ID
P14555
Uniprot Name
Phospholipase A2, membrane associated
Molecular Weight
16082.525 Da
References
  1. Geisslinger, G., & Lötsch, J. (2004). Non-steroidal anti-inflammatory drugs. In Encyclopedic reference of molecular pharmacology (pp. 667-671). Berlin: Springer. [ISBN:9783540298328]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
15-oxoprostaglandin 13-oxidase activity
Specific Function
Functions as 15-oxo-prostaglandin 13-reductase and acts on 15-keto-PGE1, 15-keto-PGE2, 15-keto-PGE1-alpha and 15-keto-PGE2-alpha with highest activity towards 15-keto-PGE2. Overexpression represses...
Gene Name
PTGR2
Uniprot ID
Q8N8N7
Uniprot Name
Prostaglandin reductase 2
Molecular Weight
38498.74 Da
References
  1. Wu YH, Ko TP, Guo RT, Hu SM, Chuang LM, Wang AH: Structural basis for catalytic and inhibitory mechanisms of human prostaglandin reductase PTGR2. Structure. 2008 Nov 12;16(11):1714-23. doi: 10.1016/j.str.2008.09.007. [PubMed:19000823]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Activator
General Function
Zinc ion binding
Specific Function
Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE...
Gene Name
PPARG
Uniprot ID
P37231
Uniprot Name
Peroxisome proliferator-activated receptor gamma
Molecular Weight
57619.58 Da
References
  1. Cho MC, Lee HS, Kim JH, Choe YK, Hong JT, Paik SG, Yoon DY: A simple ELISA for screening ligands of peroxisome proliferator-activated receptor-gamma. J Biochem Mol Biol. 2003 Mar 31;36(2):207-13. [PubMed:12689521]
  2. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA: Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997 Feb 7;272(6):3406-10. [PubMed:9013583]
Details
6. Lactoylglutathione lyase
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Catalyzes the conversion of hemimercaptal, formed from methylglyoxal and glutathione, to S-lactoylglutathione. Involved in the regulation of TNF-induced transcriptional activity of NF-kappa-B. Requ...
Gene Name
GLO1
Uniprot ID
Q04760
Uniprot Name
Lactoylglutathione lyase
Molecular Weight
20777.515 Da
References
  1. Sato S, Kwon Y, Kamisuki S, Srivastava N, Mao Q, Kawazoe Y, Uesugi M: Polyproline-rod approach to isolating protein targets of bioactive small molecules: isolation of a new target of indomethacin. J Am Chem Soc. 2007 Jan 31;129(4):873-80. [PubMed:17243824]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Other/unknown
General Function
Prostaglandin j receptor activity
Specific Function
Receptor for prostaglandin D2 (PGD2). Coupled to the G(i)-protein. Receptor activation may result in pertussis toxin-sensitive decreases in cAMP levels and Ca(2+) mobilization. PI3K signaling is al...
Gene Name
PTGDR2
Uniprot ID
Q9Y5Y4
Uniprot Name
Prostaglandin D2 receptor 2
Molecular Weight
43267.15 Da
References
  1. Hata AN, Lybrand TP, Breyer RM: Identification of determinants of ligand binding affinity and selectivity in the prostaglandin D2 receptor CRTH2. J Biol Chem. 2005 Sep 16;280(37):32442-51. Epub 2005 Jul 19. [PubMed:16030019]
  2. Hata AN, Lybrand TP, Marnett LJ, Breyer RM: Structural determinants of arylacetic acid nonsteroidal anti-inflammatory drugs necessary for binding and activation of the prostaglandin D2 receptor CRTH2. Mol Pharmacol. 2005 Mar;67(3):640-7. Epub 2004 Nov 24. [PubMed:15563582]
  3. Mathiesen JM, Ulven T, Martini L, Gerlach LO, Heinemann A, Kostenis E: Identification of indole derivatives exclusively interfering with a G protein-independent signaling pathway of the prostaglandin D2 receptor CRTH2. Mol Pharmacol. 2005 Aug;68(2):393-402. Epub 2005 May 3. [PubMed:15870392]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
General Function
Zinc ion binding
Specific Function
Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleyleth...
Gene Name
PPARA
Uniprot ID
Q07869
Uniprot Name
Peroxisome proliferator-activated receptor alpha
Molecular Weight
52224.595 Da
References
  1. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA: Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997 Feb 7;272(6):3406-10. [PubMed:9013583]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity
Specific Function
Catalyzes the conversion of aldehydes and ketones to alcohols. Catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ) and the oxidation of 9-alpha,11-beta-PGF2 to PGD2....
Gene Name
AKR1C3
Uniprot ID
P42330
Uniprot Name
Aldo-keto reductase family 1 member C3
Molecular Weight
36852.89 Da
References
  1. Lovering AL, Ride JP, Bunce CM, Desmond JC, Cummings SM, White SA: Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin. Cancer Res. 2004 Mar 1;64(5):1802-10. [PubMed:14996743]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
  2. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
  3. Wang et al. (2004). Clin Pharmacol Ther. 75:191-197 [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
  2. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [PubMed:11996015]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Triglyceride lipase activity
Specific Function
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acy...
Gene Name
CES1
Uniprot ID
P23141
Uniprot Name
Liver carboxylesterase 1
Molecular Weight
62520.62 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. Mano Y, Usui T, Kamimura H: Contribution of UDP-glucuronosyltransferases 1A9 and 2B7 to the glucuronidation of indomethacin in the human liver. Eur J Clin Pharmacol. 2007 Mar;63(3):289-96. Epub 2007 Jan 24. [PubMed:17245571]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
  2. Mano Y, Usui T, Kamimura H: In vitro inhibitory effects of non-steroidal antiinflammatory drugs on UDP-glucuronosyltransferase 1A1-catalysed estradiol 3beta-glucuronidation in human liver microsomes. Biopharm Drug Dispos. 2005 Jan;26(1):35-9. [PubMed:15593333]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
Gene Name
UGT2B7
Uniprot ID
P16662
Uniprot Name
UDP-glucuronosyltransferase 2B7
Molecular Weight
60694.12 Da
References
  1. Mano Y, Usui T, Kamimura H: Contribution of UDP-glucuronosyltransferases 1A9 and 2B7 to the glucuronidation of indomethacin in the human liver. Eur J Clin Pharmacol. 2007 Mar;63(3):289-96. Epub 2007 Jan 24. [PubMed:17245571]
  2. Mano Y, Usui T, Kamimura H: Inhibitory potential of nonsteroidal anti-inflammatory drugs on UDP-glucuronosyltransferase 2B7 in human liver microsomes. Eur J Clin Pharmacol. 2007 Feb;63(2):211-6. Epub 2007 Jan 3. [PubMed:17200831]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Bertucci C, Wainer IW: Improved chromatographic performance of a modified human albumin based stationary phase. Chirality. 1997;9(4):335-40. [PubMed:9275312]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Organic anion transmembrane transporter activity
Specific Function
May act as an inducible transporter in the biliary and intestinal excretion of organic anions. Acts as an alternative route for the export of bile acids and glucuronides from cholestatic hepatocyte...
Gene Name
ABCC3
Uniprot ID
O15438
Uniprot Name
Canalicular multispecific organic anion transporter 2
Molecular Weight
169341.14 Da
References
  1. Zelcer N, Saeki T, Reid G, Beijnen JH, Borst P: Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem. 2001 Dec 7;276(49):46400-7. [PubMed:11581266]
  2. Gedeon C, Behravan J, Koren G, Piquette-Miller M: Transport of glyburide by placental ABC transporters: implications in fetal drug exposure. Placenta. 2006 Nov-Dec;27(11-12):1096-102. Epub 2006 Feb 3. [PubMed:16460798]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Atpase activity, coupled to transmembrane movement of substances
Specific Function
May be an organic anion pump relevant to cellular detoxification.
Gene Name
ABCC4
Uniprot ID
O15439
Uniprot Name
Multidrug resistance-associated protein 4
Molecular Weight
149525.33 Da
References
  1. Reid G, Wielinga P, Zelcer N, van der Heijden I, Kuil A, de Haas M, Wijnholds J, Borst P: The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9244-9. Epub 2003 Jun 30. [PubMed:12835412]
  2. Bai J, Lai L, Yeo HC, Goh BC, Tan TM: Multidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane-glutathione. Int J Biochem Cell Biol. 2004 Feb;36(2):247-57. [PubMed:14643890]
  3. Ose A, Ito M, Kusuhara H, Yamatsugu K, Kanai M, Shibasaki M, Hosokawa M, Schuetz JD, Sugiyama Y: Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood-brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4). Drug Metab Dispos. 2009 Feb;37(2):315-21. doi: 10.1124/dmd.108.024018. Epub 2008 Nov 24. [PubMed:19029202]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transporter activity
Specific Function
Isoform 1: May participate directly in the active transport of drugs into subcellular organelles or influence drug distribution indirectly. Transports glutathione conjugates as leukotriene-c4 (LTC4...
Gene Name
ABCC6
Uniprot ID
O95255
Uniprot Name
Multidrug resistance-associated protein 6
Molecular Weight
164904.81 Da
References
  1. Ilias A, Urban Z, Seidl TL, Le Saux O, Sinko E, Boyd CD, Sarkadi B, Varadi A: Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). J Biol Chem. 2002 May 10;277(19):16860-7. Epub 2002 Mar 5. [PubMed:11880368]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Wang EJ, Casciano CN, Clement RP, Johnson WW: Active transport of fluorescent P-glycoprotein substrates: evaluation as markers and interaction with inhibitors. Biochem Biophys Res Commun. 2001 Nov 30;289(2):580-5. [PubMed:11716514]
  2. Faassen F, Vogel G, Spanings H, Vromans H: Caco-2 permeability, P-glycoprotein transport ratios and brain penetration of heterocyclic drugs. Int J Pharm. 2003 Sep 16;263(1-2):113-22. [PubMed:12954186]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transporter activity
Specific Function
Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotre...
Gene Name
ABCC1
Uniprot ID
P33527
Uniprot Name
Multidrug resistance-associated protein 1
Molecular Weight
171589.5 Da
References
  1. Evers R, de Haas M, Sparidans R, Beijnen J, Wielinga PR, Lankelma J, Borst P: Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export. Br J Cancer. 2000 Aug;83(3):375-83. [PubMed:10917554]
  2. Hong J, Lambert JD, Lee SH, Sinko PJ, Yang CS: Involvement of multidrug resistance-associated proteins in regulating cellular levels of (-)-epigallocatechin-3-gallate and its methyl metabolites. Biochem Biophys Res Commun. 2003 Oct 10;310(1):222-7. [PubMed:14511674]
  3. Ilias A, Urban Z, Seidl TL, Le Saux O, Sinko E, Boyd CD, Sarkadi B, Varadi A: Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). J Biol Chem. 2002 May 10;277(19):16860-7. Epub 2002 Mar 5. [PubMed:11880368]
  4. Reid G, Wielinga P, Zelcer N, van der Heijden I, Kuil A, de Haas M, Wijnholds J, Borst P: The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9244-9. Epub 2003 Jun 30. [PubMed:12835412]
  5. Gedeon C, Behravan J, Koren G, Piquette-Miller M: Transport of glyburide by placental ABC transporters: implications in fetal drug exposure. Placenta. 2006 Nov-Dec;27(11-12):1096-102. Epub 2006 Feb 3. [PubMed:16460798]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity). Selectively inhibit...
Gene Name
SLCO1A2
Uniprot ID
P46721
Uniprot Name
Solute carrier organic anion transporter family member 1A2
Molecular Weight
74144.105 Da
References
  1. Shitara Y, Sugiyama D, Kusuhara H, Kato Y, Abe T, Meier PJ, Itoh T, Sugiyama Y: Comparative inhibitory effects of different compounds on rat oatpl (slc21a1)- and Oatp2 (Slc21a5)-mediated transport. Pharm Res. 2002 Feb;19(2):147-53. [PubMed:11883641]
  2. Kouzuki H, Suzuki H, Sugiyama Y: Pharmacokinetic study of the hepatobiliary transport of indomethacin. Pharm Res. 2000 Apr;17(4):432-8. [PubMed:10870987]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Substrate profile was demonstrated in vitro using human OAT1 expressed on S2 cells.
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. Mulato AS, Ho ES, Cihlar T: Nonsteroidal anti-inflammatory drugs efficiently reduce the transport and cytotoxicity of adefovir mediated by the human renal organic anion transporter 1. J Pharmacol Exp Ther. 2000 Oct;295(1):10-5. [PubMed:10991954]
  2. Jung KY, Takeda M, Kim DK, Tojo A, Narikawa S, Yoo BS, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of ochratoxin A transport by human organic anion transporters. Life Sci. 2001 Sep 21;69(18):2123-35. [PubMed:11669456]
  3. Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther. 2002 Aug;302(2):666-71. [PubMed:12130730]
  4. Hosoyamada M, Sekine T, Kanai Y, Endou H: Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. Am J Physiol. 1999 Jan;276(1 Pt 2):F122-8. [PubMed:9887087]
  5. Lu R, Chan BS, Schuster VL: Cloning of the human kidney PAH transporter: narrow substrate specificity and regulation by protein kinase C. Am J Physiol. 1999 Feb;276(2 Pt 2):F295-303. [PubMed:9950961]
  6. Sandhu P, Lee W, Xu X, Leake BF, Yamazaki M, Stone JA, Lin JH, Pearson PG, Kim RB: Hepatic uptake of the novel antifungal agent caspofungin. Drug Metab Dispos. 2005 May;33(5):676-82. Epub 2005 Feb 16. [PubMed:15716364]
  7. Kuze K, Graves P, Leahy A, Wilson P, Stuhlmann H, You G: Heterologous expression and functional characterization of a mouse renal organic anion transporter in mammalian cells. J Biol Chem. 1999 Jan 15;274(3):1519-24. [PubMed:9880528]
  8. Uwai Y, Saito H, Inui K: Interaction between methotrexate and nonsteroidal anti-inflammatory drugs in organic anion transporter. Eur J Pharmacol. 2000 Dec 1;409(1):31-6. [PubMed:11099697]
  9. Apiwattanakul N, Sekine T, Chairoungdua A, Kanai Y, Nakajima N, Sophasan S, Endou H: Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes. Mol Pharmacol. 1999 May;55(5):847-54. [PubMed:10220563]
  10. VanWert AL, Gionfriddo MR, Sweet DH: Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology. Biopharm Drug Dispos. 2010 Jan;31(1):1-71. doi: 10.1002/bdd.693. [PubMed:19953504]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. Cha SH, Sekine T, Fukushima JI, Kanai Y, Kobayashi Y, Goya T, Endou H: Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001 May;59(5):1277-86. [PubMed:11306713]
  2. Jung KY, Takeda M, Kim DK, Tojo A, Narikawa S, Yoo BS, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of ochratoxin A transport by human organic anion transporters. Life Sci. 2001 Sep 21;69(18):2123-35. [PubMed:11669456]
  3. Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther. 2002 Aug;302(2):666-71. [PubMed:12130730]
  4. Ohtsuki S, Kikkawa T, Mori S, Hori S, Takanaga H, Otagiri M, Terasaki T: Mouse reduced in osteosclerosis transporter functions as an organic anion transporter 3 and is localized at abluminal membrane of blood-brain barrier. J Pharmacol Exp Ther. 2004 Jun;309(3):1273-81. Epub 2004 Feb 4. [PubMed:14762099]
  5. Mori S, Takanaga H, Ohtsuki S, Deguchi T, Kang YS, Hosoya K, Terasaki T: Rat organic anion transporter 3 (rOAT3) is responsible for brain-to-blood efflux of homovanillic acid at the abluminal membrane of brain capillary endothelial cells. J Cereb Blood Flow Metab. 2003 Apr;23(4):432-40. [PubMed:12679720]
  6. Kusuhara H, Sekine T, Utsunomiya-Tate N, Tsuda M, Kojima R, Cha SH, Sugiyama Y, Kanai Y, Endou H: Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain. J Biol Chem. 1999 May 7;274(19):13675-80. [PubMed:10224140]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Organic anion transmembrane transporter activity
Specific Function
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
Canalicular multispecific organic anion transporter 1
Molecular Weight
174205.64 Da
References
  1. Gedeon C, Behravan J, Koren G, Piquette-Miller M: Transport of glyburide by placental ABC transporters: implications in fetal drug exposure. Placenta. 2006 Nov-Dec;27(11-12):1096-102. Epub 2006 Feb 3. [PubMed:16460798]
  2. Dahan A, Amidon GL: Small intestinal efflux mediated by MRP2 and BCRP shifts sulfasalazine intestinal permeability from high to low, enabling its colonic targeting. Am J Physiol Gastrointest Liver Physiol. 2009 Aug;297(2):G371-7. doi: 10.1152/ajpgi.00102.2009. Epub 2009 Jun 18. [PubMed:19541926]
  3. Dahan A, Sabit H, Amidon GL: The H2 receptor antagonist nizatidine is a P-glycoprotein substrate: characterization of its intestinal epithelial cell efflux transport. AAPS J. 2009 Jun;11(2):205-13. doi: 10.1208/s12248-009-9092-5. Epub 2009 Mar 25. [PubMed:19319690]
  4. Kouzuki H, Suzuki H, Sugiyama Y: Pharmacokinetic study of the hepatobiliary transport of indomethacin. Pharm Res. 2000 Apr;17(4):432-8. [PubMed:10870987]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Purine nucleotide transmembrane transporter activity
Specific Function
Participates in physiological processes involving bile acids, conjugated steroids and cyclic nucleotides. Enhances the cellular extrusion of cAMP and cGMP. Stimulates the ATP-dependent uptake of a ...
Gene Name
ABCC11
Uniprot ID
Q96J66
Uniprot Name
ATP-binding cassette sub-family C member 11
Molecular Weight
154299.625 Da
References
  1. Chen ZS, Guo Y, Belinsky MG, Kotova E, Kruh GD: Transport of bile acids, sulfated steroids, estradiol 17-beta-D-glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11). Mol Pharmacol. 2005 Feb;67(2):545-57. Epub 2004 Nov 10. [PubMed:15537867]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates saturable uptake of estrone sulfate, dehydroepiandrosterone sulfate and related compounds.
Gene Name
SLC22A11
Uniprot ID
Q9NSA0
Uniprot Name
Solute carrier family 22 member 11
Molecular Weight
59970.945 Da
References
  1. Babu E, Takeda M, Narikawa S, Kobayashi Y, Enomoto A, Tojo A, Cha SH, Sekine T, Sakthisekaran D, Endou H: Role of human organic anion transporter 4 in the transport of ochratoxin A. Biochim Biophys Acta. 2002 Jun 12;1590(1-3):64-75. [PubMed:12063169]
  2. Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther. 2002 Aug;302(2):666-71. [PubMed:12130730]
  3. Cha SH, Sekine T, Kusuhara H, Yu E, Kim JY, Kim DK, Sugiyama Y, Kanai Y, Endou H: Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J Biol Chem. 2000 Feb 11;275(6):4507-12. [PubMed:10660625]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Virus receptor activity
Specific Function
The hepatic sodium/bile acid uptake system exhibits broad substrate specificity and transports various non-bile acid organic compounds as well. It is strictly dependent on the extracellular presenc...
Gene Name
SLC10A1
Uniprot ID
Q14973
Uniprot Name
Sodium/bile acid cotransporter
Molecular Weight
38118.64 Da
References
  1. Kouzuki H, Suzuki H, Sugiyama Y: Pharmacokinetic study of the hepatobiliary transport of indomethacin. Pharm Res. 2000 Apr;17(4):432-8. [PubMed:10870987]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates sodium-independent multispecific organic anion transport. Transport of prostaglandin E2, prostaglandin F2, tetracycline, bumetanide, estrone sulfate, glutarate, dehydroepiandrosterone sulf...
Gene Name
SLC22A7
Uniprot ID
Q9Y694
Uniprot Name
Solute carrier family 22 member 7
Molecular Weight
60025.025 Da
References
  1. Morita N, Kusuhara H, Sekine T, Endou H, Sugiyama Y: Functional characterization of rat organic anion transporter 2 in LLC-PK1 cells. J Pharmacol Exp Ther. 2001 Sep;298(3):1179-84. [PubMed:11504818]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. Karlgren M, Ahlin G, Bergstrom CA, Svensson R, Palm J, Artursson P: In vitro and in silico strategies to identify OATP1B1 inhibitors and predict clinical drug-drug interactions. Pharm Res. 2012 Feb;29(2):411-26. doi: 10.1007/s11095-011-0564-9. Epub 2011 Aug 23. [PubMed:21861202]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Transporter activity
Specific Function
Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
Gene Name
ABCB11
Uniprot ID
O95342
Uniprot Name
Bile salt export pump
Molecular Weight
146405.83 Da
References
  1. Pedersen JM, Matsson P, Bergstrom CA, Hoogstraate J, Noren A, LeCluyse EL, Artursson P: Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43. doi: 10.1093/toxsci/kft197. Epub 2013 Sep 6. [PubMed:24014644]

Drug created on June 13, 2005 07:24 / Updated on November 17, 2018 04:48